Microbial Translocation and HIV-Related Endothelial Dysfunction

DESCRIPTION (provided by applicant): The overall goal of this project is to establish a relationship between translocation of gut microbial products and the dysfunction of the vascular endothelium, and thus ultimately with the increased risk of cardiovascular disease that occurs in patients infected with HIV. HIV infection is known to cause depletion of gut-associated lymphoid tissue (GALT) and mucosal damage. These alterations lead to increased permeability and translocation of gut microbial products across the mucosal barrier and into the circulation. Increased circulating levels of gut microbial products, such as bacterial lipopolysaccharide (LPS), have been linked to various manifestations of vascular dysfunction in a variety of settings via endothelial cell activation and local and systemic inflammation. HIV infection itself, and the antiretroviral therapy (ART) used to treat HIV infection, have been linked to dysfunction of the vascular endothelium. Neither reliable biomarkers nor the mechanisms for this dysfunction have yet been identified. Vascular endothelial dysfunction sets the stage for and promotes the development of atherosclerotic disease. The incidence of cardiovascular disease, including myocardial infarction, is increased in patients infected with HIV. Thus, we hypothesize that increased translocation of gut microbial products leads to endothelial dysfunction in patients with HIV. If an association is found, this will justify further investigation into the pathophysiologic mechanisms underlying the link between microbial translocation and endothelial dysfunction and establish a useful biomarker to target in interventional studies. To investigate our central hypothesis, we propose these Specific Aims: Specific Aim #1: Establish a relationship between circulating levels of microbial translocation markers and endothelial dysfunction in HIV-infected subjects. We propose to combine 2 well-characterized groups of study subjects from investigations completed by the AIDS Clinical Trials Group (ACTG 5152s, N=82) and at Indiana University (IU study, N=96) who underwent a series of detailed evaluations which included measures of endothelial function by B-mode ultrasound of the brachial artery (flow-mediated dilation, or FMD). Using saved frozen specimens, levels of circulating LPS, soluble CD14, and bacterial 16S ribosomal DNA (16S rDNA) will be measured. These biomarkers will be correlated with FMD to investigate the relationship of endothelial dysfunction with gut microbial translocation and systemic immune activation and inflammation. Specific Aim #2: Examine the relationship between treatment-related improvement in endothelial dysfunction and changes in the levels of circulating gut microbial markers. We hypothesize that ART-related decreases in microbial translocation will result in improved endothelial function (greater FMD values). In ACTG 5152s, ART- treated subjects experienced an improvement in endothelial dysfunction. We will correlate changes in circulating levels of microbial translocation markers after initiating ART with changes in brachial FMD at 24 weeks.

DESCRIPTION (provided by applicant): The overall goal of this project is to establish a relationship between translocation of gut microbial products and the dysfunction of the vascular endothelium, and thus ultimately with the increased risk of cardiovascular disease that occurs in patients infected with HIV. HIV infection is known to cause depletion of gut-associated lymphoid tissue (GALT) and mucosal damage. These alterations lead to increased permeability and translocation of gut microbial products across the mucosal barrier and into the circulation. Increased circulating levels of gut microbial products, such as bacterial lipopolysaccharide (LPS), have been linked to various manifestations of vascular dysfunction in a variety of settings via endothelial cell activation and local and systemic inflammation. HIV infection itself, and the antiretroviral therapy (ART) used to treat HIV infection, have been linked to dysfunction of the vascular endothelium. Neither reliable biomarkers nor the mechanisms for this dysfunction have yet been identified. Vascular endothelial dysfunction sets the stage for and promotes the development of atherosclerotic disease. The incidence of cardiovascular disease, including myocardial infarction, is increased in patients infected with HIV. Thus, we hypothesize that increased translocation of gut microbial products leads to endothelial dysfunction in patients with HIV. If an association is found, this will justify further investigation into the pathophysiologic mechanisms underlying the link between microbial translocation and endothelial dysfunction and establish a useful biomarker to target in interventional studies. To investigate our central hypothesis, we propose these Specific Aims: Specific Aim #1: Establish a relationship between circulating levels of microbial translocation markers and endothelial dysfunction in HIV-infected subjects. We propose to combine 2 well-characterized groups of study subjects from investigations completed by the AIDS Clinical Trials Group (ACTG 5152s, N=82) and at Indiana University (IU study, N=96) who underwent a series of detailed evaluations which included measures of endothelial function by B-mode ultrasound of the brachial artery (flow-mediated dilation, or FMD). Using saved frozen specimens, levels of circulating LPS, soluble CD14, and bacterial 16S ribosomal DNA (16S rDNA) will be measured. These biomarkers will be correlated with FMD to investigate the relationship of endothelial dysfunction with gut microbial translocation and systemic immune activation and inflammation. Specific Aim #2: Examine the relationship between treatment-related improvement in endothelial dysfunction and changes in the levels of circulating gut microbial markers. We hypothesize that ART-related decreases in microbial translocation will result in improved endothelial function (greater FMD values). In ACTG 5152s, ART- treated subjects experienced an improvement in endothelial dysfunction. We will correlate changes in circulating levels of microbial translocation markers after initiating ART with changes in brachial FMD at 24 weeks.